10 Feb 2018

[9 April 2024 Editor’s note: This paper has been retracted by the authors.]

Loss of pericytes, delicate cells that surround the smallest blood vessels in the brain, may contribute to white-matter disease, a breakdown of the myelinated neurons in the brain. That’s according to a paper in the February 5 Nature Medicine. Scientists led by Berislav Zlokovic, University of Southern California, Los Angeles, report that the blood-brain barrier breaks down in mice deficient in pericytes. Plasma proteins, such as fibrinogen, then deposit in the white matter, blood flow there slows, and ultimately myelin and neurons degenerate. The results suggest that pericytes, which die off in diseases such as Alzheimer’s, are a cornerstone of the physiological health of the white matter.

“In Alzheimer’s, the blood-brain barrier breaks down, white-matter hyperintensities appear, and fibrinogen deposits, all of which contribute somewhat to the disease,” said Sidney Strickland of The Rockefeller University in New York. “It’s really interesting to tie them together with these vascular cells.” Strickland was not involved in the study.

Charles DeCarli, University of California, Davis, said this is further evidence of a close relationship between the vascular system and neural integrity, though he thinks it is unclear how these findings fit with AD, because the researchers didn’t experiment on any mouse models of the disease. 

White-matter disease destroys the axon-insulating myelin sheaths that give white matter its name. It may contribute to the cognitive deficits seen in Alzheimer’s disease. Because myelin deterioration has been linked to disease of small blood vessels that feed white matter, Zlokovic and colleagues wondered if perictyes played a part (Wardlaw et al., 2013). These cells die in AD, stroke, mild dementia, and CADASIL, a familial small-vessel disease often accompanied by cognitive impairment. Pericytes control the permeability of the blood-brain barrier and possibly blood flow in the gray matter, as Zlokovic and others have reported, but their influence over white matter was a mystery (see Armulik et al., 2010; Hall et al., 2014). 

To investigate, joint first authors Axel Montagne, Angeliki Nikolakopoulou, and Zhen Zhao monitored how myelinated tracts held up over 48 weeks in pericyte-deficient mice. They used a variety of longitudinal magnetic resonance imaging techniques miniaturized for mice to examine animals expressing a mutated platelet-derived growth factor receptor β gene. PDGFβ supports pericyte migration. When the mutants were two weeks old they mustered only 75 percent as many pericytes as did wild-type mice, and progressively fewer as they got older. 

The researchers found that as the number of pericytes dwindled, the capillaries supporting the white-matter tracts of the corpus callosum, internal capsule, cingulum, and external capsule became more permeable. This began when the mice were about four to six weeks old. At the same time, fibrinogen, a blood-clotting protein, crossed the blood-brain barrier and formed deposits in the white matter. White-matter tracts also steadily lost blood flow.

Other changes followed soon after. By 12 weeks, oligodendrocyte density fell by a third, myelin began to break down, and axon density dropped by more than a quarter in white-matter tracts (see image above). All three problems worsened over the next 36 weeks. Gaps began to open around the blood vessels—a sign of small-vessel disease. The mice ran sluggishly and remembered poorly compared to controls. Gray matter was not spared, either. A quarter of cells in the cortices and hippocampi of 36- to 48-week-old PDGFβ mutants had 25 percent fewer neurons than did controls.

The reasons for the cell death were unclear, but could have to do with increasing hypoxia that the researchers detected in the white matter. Cell death could also have come from autophagy-induced apoptosis, claim the authors, which they found was spurred on in cultured oligodendrocytes and pericytes by fibrinogen. If the researchers quelled systemic levels of fibrinogen in the PDGFRβ mutant mice, more pericytes survived. When they increased fibrinogen in the blood, which then crossed into the brain, more pericytes and oligodendrocytes died. “A pathogenic role of fibrinogen appears to be validated and extended in pericyte-deficient mice tested in this study,” said Katerina Akassoglou, University of California, San Francisco. The authors present an interesting new cellular mechanism of fibrinogen action in pericyte and oligodendrocyte apoptosis, namely through autophagy, she added.

All told, the authors conclude that pericytes, in addition to their established roles in the gray matter, help maintain the health of the white matter. Interestingly, the authors examined postmortem brain tissue from 16 AD patients and 15 controls, to see if the patients showed pathologies similar to the mice. Indeed, patients had half as many pericytes and oligodendrocytes in the subcortical white matter as did controls, more deposits of fibrinogen, and evidence of myelin destruction.

Scientists pointed out that controversy exists about whether these mice lack only pericytes, or if they lack other types of cells as well. “It could be that something else in this mouse is altered,” said Costantino Iadecola, Weill Cornell Medical College, New York. Even if pericyte death causes white-matter disease, and that holds true in humans, it could be that this death is secondary to another factor causing cognitive problems, not the primary upstream issue, he said. Nevertheless, he said it is clear from the findings that the health of the pericyte is critical for the health of the white matter.

“The importance of white-matter dysfunction is generally underappreciated in aging and dementia,” said Gareth Howell, Jackson Laboratory, Bar Harbor, Maine. “This study adds further weight behind the idea that trying to improve cerebrovascular health is likely to be of huge benefit to reduce risk for dementia.” He emphasized that there are likely myriad other ways to bolster the strength of the blood-brain barrier and vascular health than targeting pericytes.—Gwyneth Dickey Zakaib

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References

Paper Citations

1. Montagne A, Nikolakopoulou AM, Zhao Z, Sagare AP, Si G, Lazic D, Barnes SR, Daianu M, Ramanathan A, Go A, Lawson EJ, Wang Y, Mack WJ, Thompson PM, Schneider JA, Varkey J, Langen R, Mullins E, Jacobs RE, Zlokovic BV. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med. 2018 Mar;24(3):326-337. Epub 2018 Feb 5 PubMed. RETRACTED
2. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O'Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge Rv, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M, STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013 Aug;12(8):822-38. PubMed.
3. Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C. Pericytes regulate the blood-brain barrier. Nature. 2010 Nov 25;468(7323):557-61. Epub 2010 Oct 13 PubMed.
4. Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O'Farrell FM, Buchan AM, Lauritzen M, Attwell D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014 Apr 3;508(7494):55-60. Epub 2014 Mar 26 PubMed.

Further Reading

Papers

1. Iadecola C. The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron. 2017 Sep 27;96(1):17-42. PubMed.
2. Strickland S. Blood will out: vascular contributions to Alzheimer's disease. J Clin Invest. 2018 Feb 1;128(2):556-563. PubMed.

News

1. Finally, a Dye to Visualize Pericyte Function 19 May 2017
2. What’s Up With the Vasculature in Dementia? 10 May 2016
3. Smooth Muscle Cells, Not Pericytes, Control Brain Blood Flow 26 Jun 2015
4. Pericytes Don’t Go With the Flow—They Change It 3 Feb 2017